Structures of Naked Mole-Rat, Tuco-Tuco, and Guinea Pig Ribosomes: Is rRNA Fragmentation Linked to Translational Fidelity?
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ABSTRACT:
ORGANISM(S): Ctenomys talarum
PROVIDER: GSE306918 | GEO | 2026/03/12
REPOSITORIES: GEO
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Project description:Ribosome biogenesis is a complex and intricate process involving multiple factors. A plethora of auxiliary proteins assist the correct assembly of rRNA and ribosomal proteins into mature ribosomes. Defects in this process cause dysfunctional ribosomes which may alter protein synthesis and impair cell fitness. Despite its importance, yet we are lacking mechanistic details of ribosome biogenesis. Here we show that the widely-conserved RNA chaperone Hfq, which is an important post-transcriptional regulator in sRNA-mRNA basepairing in Escherichia coli, plays a critical role in rRNA processing and consequently ribosome assembly. Hfq binds the 17S rRNA precursor and facilitates its correct processing and folding to mature 16S rRNA. Strikingly, Hfq depletion decreases the pool of mature 70S ribosomes. Mutations in residues located in the distal face of Hfq render reduced ribosome levels in contrast to mutations in the proximal and rim surfaces which govern interactions with the sRNAs. Our results indicate that the described Hfq-dependent regulation of ribosomes is independent of its function as sRNA-regulator. Furthermore, we observed that inactivation of Hfq compromises translation efficiency and fidelity, both features of aberrantly assembled ribosomes. Our work expands the functions of Hfq beyond its function in small RNA-mediated regulation and unveil a novel role of Hfq as crucial auxiliary factor in ribosome biogenesis and translation.
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Project description:Osteoarthritis (OA) is a chronic debilitating joint disease which is strongly associated with ageing. OA involves pathological cellular processes in all joint structures and affects articular cartilage integrity, leading to dysfunctional joint articulation. The biomolecular processes that catalyze the disturbances in the articular chondrocyte phenotype leading to OA are poorly understood, and it is expected that a comprehensive understanding of the avenues leading to catabolic changes and disruption of articular chondrocyte homeostasis will provide important cues for future treatments of the condition. Chondrocytes are specialized secretory cells with highly active protein translational machinery, enabling the synthesis and maintenance of the protein-rich cartilage extracellular matrix (ECM). Disturbances in chondrocyte protein translation in cartilage development and OA are connected to mTOR activity, ER stress, unfolded protein response (UPR)and CHOP-mediated apoptosis. These responses change the downstream translational activity of the biosynthesized ribosome. The assembled mammalian ribosome is built from ribosomal RNAs (rRNAs), together with more than 80 different protein subunits. At the heart of the ribosome, the 18S rRNA guides the decoding of the mRNA message, while an ancient ribozyme activity in the 28S rRNA forms the core of the peptidyltransferase center that polymerizes the amino acid sequence encoded by the mRNA into functional proteins. Post-transcriptional maturation of rRNAs is an integral part of the biosynthesis of ribosomes and ribonucleolytic processing of the major 47S rRNA precursor into mature 18S, 5.8S, and 28S rRNAs is rate limiting for ribosome biogenesis. The U3 small nucleolar RNA (snoRNA) is an evolutionarily highly conserved box C/D-class snoRNA which catalyzes the endoribonucleolytic processing of the 5’ external transcribed spacer (ETS) of the 47S pre-rRNA by base complementarity-guided pre-rRNA substrate recognition and plays a crucial role in the maturation of 18S rRNA. Although extensively studied in yeast, it was only recently demonstrated that U3 snoRNA is indispensable for rRNA maturation in human cells. Pathways controlling ribosome activity have previously been described in the regulation of chondrocyte homeostasis. We here now postulate that not only ribosome activity is involved in chondrocyte homeostasis, but that OA pathophysiological situations can also cause alterations in chondrocyte ribosome biogenesis with consequences for cellular protein translation. Since U3 snoRNA-driven rRNA production is rate-limiting in ribosome biogenesis, we hypothesized that the U3 snoRNA is critical for chondrocyte homeostasis. In this study we therefor aimed to determine whether OA pathophysiological conditions interact with chondrocyte U3 snoRNA levels, thereby influencing rRNA levels and chondrocyte translation capacity.
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